This is an amended application in which we propose four projects in years 31 to 35 of a successful Program to explore the molecular basis of viral and cellular transformation. In this revised application, we have deleted the two lower ranking projects and one core. The four remaining laboratories will carry out investigations into the role of viral gone products, interacting cellular proteins, and mutagenesis in cell transformation. Dr. Miller will continue his studies on the mechanism of viral transactivators that disrupt herpesvirus latency. Dr. DiMaio will continue his analysis of the role of the human papillomavirus E6 and E7 oncogenes in maintaining the proliferation of human cervical cancer cells, with a particular emphasis on determining the molecular basis for induced senescence that occurs upon oncogene repression. In a project centered on mutagenesis, Dr. Sweasy will continue her analysis of cancer-associated DNA polymerase B mutants and their ability to transform cells. Finally, Dr. Steitz will continue her studies establishing the biochemical activities of tumor virus-encoded small RNAs and determining their effects on host cell function. In addition, an administrative core and a scientific core will provide essential services to the Program. This Program represents the significant commitment of the Yale University School of Medicine and the participating investigators to studies that will have direct relevance to understanding the cause of human cancer.